11-47341204-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_000256.3(MYBPC3):c.1831G>A(p.Glu611Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,599,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:8

Conservation

PhyloP100: 7.48

Variant links:

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain Ig-like C2-type 4 (size 89) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 11-47341204-C-T is Pathogenic according to our data. Variant chr11-47341204-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180955.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=7, Pathogenic=1}. Variant chr11-47341204-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1831G>A	p.Glu611Lys	missense_variant	Exon 19 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.1831G>A	p.Glu611Lys	missense_variant	Exon 19 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1831G>A	p.Glu611Lys	missense_variant	Exon 18 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1831G>A		non_coding_transcript_exon_variant	Exon 19 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000134

AC:

AN:

223916

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

121152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000995

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1447508

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000145

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PS4:Moderate, PM2:Supporting -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:4

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: PMID: 23054336, 23283745, 24111713, 28971120, 30297972, 30847666, 31513939, 32369506). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene (PMID: 23054336). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094), an individual affected with noncompaction cardiomyopathy (PMID: 29447731), and in an individual affected with an unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 6/255294 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 611 of the MYBPC3 protein (p.Glu611Lys). This variant is present in population databases (rs730880555, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy, or noncompaction cardiomyopathy (PMID: 21750094, 23054336, 23283745, 24111713, 29447731, 30847666, 31513939, 32369506, 36264615). ClinVar contains an entry for this variant (Variation ID: 180955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4

Pathogenic:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1Uncertain:1

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Pathogenic:1Uncertain:1

Aug 02, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MYBPC3 c.1831G>A (p.Glu611Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is located in the Immunoglobulin I domain (InterPro). Other missense variants around this region have also been reported in HCM patients, such as p.Tyr614Cys, p.Asp610Val, p.Asp610His, p.Asp610Asn, p.Ala609Val, etc., suggesting a notion that the region is important for protein function; however they have conflicting interpretations of pathogenicity ranging from pathogenic to uncertain significance in ClinVar. This variant is absent in 52198 control chromosomes but has been reported in at least nine patients (2 DCM, 7 HCM) from multiple countries. However, there are no co-segregation studies in literature, nor are functional studies. One DCM patient was not comprehensively genotyped (Waldmuller_2014) while another DCM patient also has unspecified mutation(s) (Wang_2014). Thus, it may be possible that it is HCM-specific mutation. This variant was also found in one HCM patient who also carried another frameshift mutation in the same gene; however, phenotypic severity of the patient is not specified. One clinical lab has classified it as pathogenic. Taken together, this variant is classified as Probable Disease Variant (or Likely Pathogenic). -

Aug 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E611K variant (also known as c.1831G>A), located in coding exon 19 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1831. The glutamic acid at codon 611 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple hypertrophic cardiomyopathy cohorts, a dilated cardiomyopathy cohort, and a noncompaction cardiomyopathy cohort; however, clinical details were limited and several had additional cardiac variants reported, including at least one patient who was also heterozygous for a pathogenic MYBPC3 alteration (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Nijenkamp LLAM et al. PLoS One, 2020 May;15:e0232427). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Feb 07, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu611Lys variant in MYBPC3 has been reported in 2 individuals with HCM (Miller 2013, Zou 2013), in 1 individual with DCM (Waldmuller 2011) and in 1 individual with non compaction cardiomyopathy (Waning 2018). Of note, one of these individuals with HCM also carried a pathogenic variant in MYBPC3 (Miller 2013). It is present in CLinVar (ID 180955) (conflicting interpretations). The p.Glu611Lys variant was also identified in 1/27268 of South Asian chromosomes in gnomAD. Computational prediction tools and conservation analysis suggest that the p.Glu611Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu611Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

CardioboostCm

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

-0.078

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0070

D;.;D

Sift4G

Uncertain

0.029

D;D;D

Vest4

0.98

MVP

0.90

MPC

0.80

ClinPred

0.97

GERP RS

4.6

Varity_R

0.45

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over